Provocative Question 3: Summary/Abstract This proposal addresses Provocative Question #3, ?Do genetic interactions between germline variants and somatic mutations contribute to differences in tumor evolution?? The new 2016 WHO Classification of Tumors of the Central Nervous System utilizes two somatic alterations to molecularly classify adult diffuse glioma: IDH mutation and 1p/19q codeletion. We and others have shown that TERT promoter mutation further classifies gliomas into molecular subtypes with distinct clinical characteristics. In addition, during the last five years much has been learned about the germline predisposition to gliomas: genome-wide association studies (GWAS) have revealed that 25 regions in 24 genes are associated with glioma development. Our group identified many of these associations and fine-mapped two of them (MYC/CCDC26 and TP53) and demonstrated that the MYC/CCDC26 variant (rs55705857) is associated with IDH-mutant gliomas. Indeed we found rs55705857 to have an odds ratio>6 for development of IDH-mutated glioma and lowers the age of onset by ~10 years. It is clear that the risk allele of rs55705857 interacts with somatic IDH-mutation to accelerate low-grade glioma development. We hypothesize that germline variants interact with somatic alterations to accelerate the development of IDH-mutant and IDH wild-type gliomas. Our published and preliminary data provide strong evidence in support of this hypothesis; but it must be explored further. While each of the known 25 regions has been evaluated with respect to risk of the 2016 WHO molecular subtypes, an unbiased GWAS has yet to be performed. Thus, Aim 1 will cost- effectively utilize previously-collected GWAS data to identify novel germline variants that are associated with the WHO subtypes in order to provide better patient risk assessment. Aim 2 will translate these findings into the clinic by integrating the germline and somatic alterations to determine associations with patient survival. Lastly, Aim 3 will use functional genomics to begin to understand the mechanisms by with rs55705857 and other variants accelerate IDH-mutant glioma.